Innovative technology could treat cancer more selectively and effectively

Innovative technology could treat cancer more selectively and effectively

Treating cancer more specifically and effectively – this could be achieved with an innovative technology that research teams at the Leibniz Research Institute for Molecular Pharmacology (FMP) and the Ludwig Maximilian University of Munich (LMU) have developed. The process turns proteins and antibodies into stable, highly functional drug transporters that can detect and kill tumor cells.

Classic chemotherapy for cancer treatment is based on toxic substances that are particularly effective on rapidly dividing cells. However, since healthy tissue is also dependent on cell division, treatment with chemotherapeutic substances is often accompanied by serious side effects. A dose sufficient to completely remove the tumor would, in many cases, be too toxic to administer to a sick person. With more modern approaches it is now possible to transport active ingredients (Drugs) in the body in a targeted manner to the site of action, for example by linking a drug with an antibody, which can distinguish cancer cells from healthy tissue through changes on the cell surface. Five of themAntibody-drug conjugates (ADCs)are already on the market.

However, these ADCs lose a large part of their “toxic charge” on the way to the cancer cell. The substances (medications) enter the bloodstream and dangerous side effects can occur. A stable connection between drug and antibody would therefore be extremely desirable. This is exactly what the researchers – a team led by Professor Christian Hackenberger from the FMP and Professor Heinrich Leonhardt from the LMU Biozentrum – focused on. Their results were published in the renowned journal “Angewandte Chemie”: The development of methods and the application of these methods to selective drug delivery are presented in two consecutive articles.

The new drug transporters allow for lower doses and less severe side effects

“We have developed an innovative technology that makes it possible to bind native proteins and antibodies to complex molecules such as fluorescent dyes or drugs more easily and more stably than ever before,” reports Marc-André Kasper, researcher in Christian Hackenberger’s group. The researchers discovered the outstanding properties of unsaturated phosphorus (V) compounds and took advantage of them. These phosphonamides bind a desired modification - for example, an anticancer agent - exclusively to the amino acid cysteine, in a protein or antibody. Since cysteine ​​is a very rare naturally occurring amino acid, the number of modifications per protein can be controlled very effectively, which is essential for the construction of drug conjugates. In addition, phosphonamides can be easily incorporated into complex chemical compounds. “However, the greatest achievement of the new method is that the resulting compound is stable even during blood circulation,” says Marc-André Kasper. The ADCs on the market cannot do this.

To test its applicability in targeted drug delivery, the researchers directly compared their technology with the FDA-approved ADC Adcetris®. The drug was recreated as accurately as possible with the same antibody and active ingredient; the only difference was that the innovative phosphonamidate linkage was used. When applied to blood serum, the researchers observed that their modified ADC lost significantly less active ingredient over a period of days. They also used the new technology in experiments with mice to combat Hodgkin's lymphoma. The preparation proved to be more effective than conventional medications. "From our results, we conclude that phosphonamidate-linked drug transporters can be administered at lower doses and that side effects can be further reduced. Thus, the technology has great potential to replace current methods to develop more effective and safer ADCs in medicine." future,” says FMP group leader Christian Hackenberger.

In the next step, the research groups will continue their efforts to develop ADCs based on phosphonamide data. Preclinical studies, which are essential for treating patients, are already underway. The promising start-up company Tubulis, which was awarded the Leibniz Founder's Prize last year, acts as a platform for further development to market readiness.

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